Pregnancy is a unique condition in the life history of islet beta-cells. At this time there is an increased need for insulin secretion at normal glucose concentrations. This demand is met by major alterations in islet structure and function. The most important are: (a) an increase in glucose-stimulated insulin secretion (4-10 fold at normal blood glucose levels); (b) a lowering of the threshold for glucose-stimulated insulin secretion:and (c) increased beta-cell proliferation. Using lactogenic hormones from the same species (i.e., placental lactogen or prolactin which share a common receptor), we have shown that these hormones induce all of the changes in islets that occur during pregnancy. The common theme in this project is the PRL signaling pathway and how it changes insulin secretion, islet cell division and how lipids interact with this process during pregnancy. Using islets from pregnancy and islets treated with lactogenic hormones in vitro we will determine: (1) Why prolactin (PRL) receptor activation is so effective in enhancing islet function? (2) How PRL receptor activation increases insulin secretion? (3) How PRL receptor activation increases islet cell growth? (4) How lipids interact with islets in the presence of lactogens? (5) How complete is our understanding of the PRL receptor/JAK/STAT pathway in accounting for the changes in islet function during pregnancy? The overall goal is to understand the cellular mechanisms responsible for increasing islet function during pregnancy. This information will provide insight into the long-term regulation of islet function and beta-cell mass in the maintenance of normal blood glucose. Failure of islets to adapt to the increased need for insulin during pregnancy leads to gestational diabetes, a condition that is detrimental to normal fetal development as well as the health of the mother. Understanding the regulation of beta-cell glucose sensitivity is critical for understanding the progression of events that lead to gestational and type Il diabetes.
Showing the most recent 10 out of 32 publications
